ABSTRACT Eosinophilic esophagitis (EoE) is a chronic immune system disease. It has been identified only in the past two decades, but is now considered a major cause of esophageal disorder in both pediatric and adult population. The current proposal is the extension of our studies that provided novel findings including the role of IL-15 responsive iNKT cells, significance of IL-18 in IL-15 induced esophageal eosinophilia, the chemoattractant role of nerve cells derived neuropeptide VIP in EoE, and most importantly we reported a critical role IL-18 to transform IL-5 generated nave eosinophils to CD274 expressed pathogenic eosinophils. The proposed extended studies will now establish the physiological role of IL-18 and VIP in eosinophils and mast cells accumulation and degranulation in and beyond the epithelial mucosa that promotes esophageal functional abnormalities including motility dysfunction in chronic EoE. The mechanisms driving the eosinophil and mast cell accumulation, activation and degranulation in the muscular mucosa is yet not fully understood. Notably, no evidence indicates that muscle or neuronal cells are the sources of eotaxin-1, -2 or -3. Even after a decade of reported highly induced eotaxin-3 and its correlation with esophageal eosinophilia, yet the direct physiological significance of eotaxin--3 is not established in EoE. Therefore, it is critical to understand the role of tissue specific IL-18 induction and the mechanisms operational in the trafficking and accumulation of IL-18 transformed pathogenic eosinophils and mast cells in and beyond the epithelial mucosa. Our reports indicates that eosinophils and mast cells accumulation promotes epithelial, subepithelial and muscular mucosa fibrosis, muscle cell hyperplasia and esophageal functional abnormalities in human EoE. Most recently, we reported that eosinophils accumulate adjacent to nerve cells and neuroendocrine cell-derived vasoactive intestinal peptide has a chemoattractant role for eosinophils similar to the eotaxin(s). In addition, most recently both in vitro and in vivo, we showed that VIP receptor antagonist restrict eosinophils motility. Therefore, our extended grant studies will test the hypotheses that IL-18 and a neuroendocrine cell-derived chemoattractant vasoactive intestinal peptide is critical for the maturation, activation, and accumulation of eosinophils and mast cells in each segment of the esophagus and are the key for the development of fibrosis associated strictures and motility dysfunction. Accordingly, we propose three specific aims to establish the mechanistic pathways involved in IL-18-driven eosinophil and mast cell maturation, activation, and degranulation in each segment of the esophageal mucosa (AIM I); tissue-specific IL-18 induction is critical in promoting EoE pathogenesis (AIM II) and lastly, establish the role of neuroendocrine cell-derived vasoactive intestinal peptide in eosinophil and mast cell accumulation and degranulation within the muscular mucosa that promote esophageal functional abnormalities including stricture development and motility dysfunction in EoE (Aim III).